The overall aim of the proposed research is to examine effects of shearing stress on histamine metabolism in both aortic endothelium and the aortic wall in an attempt to gain insight into (1) intrinsic systems regulating large vessel transmural permeability, and (2) reasons for preferential localization of atheroma in regions of the arterial tree exposed to locally elevated, chronically applied hemodynamic stresses. Underlying the entire scope of the proposed research are the assumptions that endothelial injury is a primary causative factor in atherosclerosis, that shearing stresses imposed upon the aortic wall in general and endothelium specifically by flowing blood may represent an injurious stimulus, that aortic transmural permeability is influenced by intrinsic aortic histamine metabolism, and that the initial arterial lesion may in part represent a prolonged inflammatory response mediated by aortic histidine decarboxylase. It is believed that local induction of histamine synthesis in such regions may represent mechano-physiological coupling whereby artery metabolism is coupled to circulatory dynamics. The specific aims of the proposed research may be summarized as follows. First, normal values will be established for the histidine decarboxylase system in selected regions of whole aorta and aortic endothelium in dogs. Second, histidine metabolism, with specific attention given to synthetic pathways in above tissue preparations, will be examined following exposure to shearing stresses produced by changes in blood flow velocity induced by changes in the aortic lumenal diameter via an inserted balloon catheter. Finally, these metabolic changes will be correlated with changes in aortic wall permeability and endothelial integrity through the use of quantitative dye markers and histological examination of tissue sections.